JPS6131097B2 - - Google Patents
Info
- Publication number
- JPS6131097B2 JPS6131097B2 JP52083128A JP8312877A JPS6131097B2 JP S6131097 B2 JPS6131097 B2 JP S6131097B2 JP 52083128 A JP52083128 A JP 52083128A JP 8312877 A JP8312877 A JP 8312877A JP S6131097 B2 JPS6131097 B2 JP S6131097B2
- Authority
- JP
- Japan
- Prior art keywords
- erythro
- threo
- dibenzyloxyphenyl
- serine
- mineral acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 60
- 239000011707 mineral Substances 0.000 claims description 60
- 239000002253 acid Substances 0.000 claims description 53
- 150000003839 salts Chemical class 0.000 claims description 53
- GZLRNTMXOXBIRR-UHFFFAOYSA-N 2-azaniumyl-3-[3,4-bis(phenylmethoxy)phenyl]-3-hydroxypropanoate Chemical compound C=1C=CC=CC=1COC1=CC(C(O)C(N)C(O)=O)=CC=C1OCC1=CC=CC=C1 GZLRNTMXOXBIRR-UHFFFAOYSA-N 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 12
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 229940071870 hydroiodic acid Drugs 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical class OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 3
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 27
- GIZSHQYTTBQKOQ-UHFFFAOYSA-N threo-Syringoylglycerol Chemical compound COC1=CC(C(O)C(O)CO)=CC(OC)=C1O GIZSHQYTTBQKOQ-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 15
- 239000013078 crystal Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- -1 dibenzyloxyphenyl Chemical group 0.000 description 4
- BHECBAHOCJNIEL-FQEVSTJZSA-N (2s)-2-[3,4-bis(phenylmethoxy)anilino]-3-hydroxypropanoic acid Chemical compound C=1C=CC=CC=1COC1=CC(N[C@@H](CO)C(O)=O)=CC=C1OCC1=CC=CC=C1 BHECBAHOCJNIEL-FQEVSTJZSA-N 0.000 description 3
- WTBFLCSPLLEDEM-JIDRGYQWSA-N 1,2-dioleoyl-sn-glycero-3-phospho-L-serine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC WTBFLCSPLLEDEM-JIDRGYQWSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000010575 fractional recrystallization Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- GZLRNTMXOXBIRR-HMTLIYDFSA-N (2s)-2-amino-3-[3,4-bis(phenylmethoxy)phenyl]-3-hydroxypropanoic acid Chemical compound C=1C=CC=CC=1COC1=CC(C(O)[C@H](N)C(O)=O)=CC=C1OCC1=CC=CC=C1 GZLRNTMXOXBIRR-HMTLIYDFSA-N 0.000 description 1
- XDDLXZHBWVFPRG-UHFFFAOYSA-N 3,4-bis(phenylmethoxy)benzaldehyde Chemical compound C=1C=CC=CC=1COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 XDDLXZHBWVFPRG-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Description
【発明の詳細な説明】
本発明はスレオ−、エリスロ−３−（３・４−
ジベンジルオキシフエニル）セリンの効果的かつ
工業的な分離法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to threo-, erythro-3-(3,4-
This invention relates to an effective and industrial method for separating dibenzyloxyphenyl)serine.
更に詳しくは、スレオ−、エリスロ−３−
（３・４−ジベンジルオキシフエニル）セリンを
鉱酸（ここで鉱酸とは塩酸、臭化水素酸、ヨウ化
水素酸または硝酸を意味し、以下同じ意味を有す
る）で処理し、得られるスレオ−３−（３・４−
ジベンジルオキシフエニル）セリンの鉱酸塩とエ
リスロ−３−（３・４−ジベンジルオキシフエニ
ル）セリンの鉱酸塩との水、エタノール、イソプ
ロパノールもしくはこれらの混合溶媒中での溶解
度差を利用することにより、スレオ−３−（３・
４−ジベンジルオキシフエニル）セリンの鉱酸塩
とエリスロ−３−（３・４−ジベンジルオキシフ
エニル）セリンの鉱酸塩とに分離し、必要に応
じ、各々の鉱酸塩を分解することにより対応する
スレオ、あるいはエリスロ−３−（３・４−ジベ
ンジルオキシフエニル）セリンを得ることを特徴
とするスレオ、エリスロ−３−（３・４−ジベン
ジルオキシフエニル）セリンの分離法に関するも
のである。 For more details, see Threo-, Erythro-3-
(3,4-dibenzyloxyphenyl)serine is treated with mineral acid (mineral acid here means hydrochloric acid, hydrobromic acid, hydroiodic acid or nitric acid, hereinafter the same meaning), and the obtained Threo-3-(3・4-
The difference in solubility between mineral acid salts of dibenzyloxyphenyl) serine and erythro-3-(3,4-dibenzyloxyphenyl) serine in water, ethanol, isopropanol, or a mixed solvent thereof. By using it, Threo-3-(3・
Separate into mineral acid salts of 4-dibenzyloxyphenyl) serine and mineral acid salts of erythro-3-(3,4-dibenzyloxyphenyl) serine, and decompose each mineral acid salt as necessary. of threo or erythro-3-(3,4-dibenzyloxyphenyl)serine, characterized in that the corresponding threo or erythro-3-(3,4-dibenzyloxyphenyl)serine is obtained by It concerns separation methods.
本発明方法によつて得られる生成物、即ち、ス
レオ−あるいはエリスロ−３−（３・４−ジベン
ジルオキシフエニル）セリンもしくは各々の鉱酸
塩は脱ベンジル化反応により、対応するスレオ
−、あるいはエリスロ−３−（３・４−ジヒドロ
キシフエニル）セリン（以下、DOPSと略称す
る）、もしくはスレオあるいはエリスロ−DOPS
の各々の鉱酸塩を与えることが既に知られてい
る。従つて、本発明方法はスレオ、あるいはエリ
スロ−DOPSを製造する上で非常に有用な技術を
提供することになる。 The products obtained by the process of the present invention, i.e., threo- or erythro-3-(3,4-dibenzyloxyphenyl)serine or their respective mineral acid salts, are processed by debenzylation reaction to produce the corresponding threo-, Or erythro-3-(3,4-dihydroxyphenyl)serine (hereinafter abbreviated as DOPS), or threo or erythro-DOPS
It is already known to give mineral acid salts of each of the following. Therefore, the method of the present invention provides a very useful technique for producing threo- or erythro-DOPS.
なお、このようにして得られるスレオ、あるい
はエリスロ−DOPSは生体内における重要カテコ
ールアミンであるノルエピネフリンの前駆体にな
り得るものとされており、またそのもの自身、循
環器系に関与する作用あるいは向精神作用を有し
ていることが知られている（特開昭50−49252号
公報）。 Furthermore, threo or erythro-DOPS obtained in this way is said to be a precursor of norepinephrine, which is an important catecholamine in the body, and itself has effects related to the circulatory system or psychotropic effects. (Japanese Unexamined Patent Publication No. 50-49252).
ところで、DOPSは３・４−ジベンジルオキシ
ベンズアルデヒドとグリシンの縮合により３−
（３・４−ジベンジルオキシフエニル）セリンを
経て前述の様に合成できるがこの合成法では生成
するDOPSは立体異性体であるスレオ体とエリス
ロ体の混合物として得られる。 By the way, DOPS is produced by the condensation of 3,4-dibenzyloxybenzaldehyde and glycine.
It can be synthesized as described above via (3,4-dibenzyloxyphenyl)serine, but in this synthesis method, the generated DOPS is obtained as a mixture of stereoisomers, threo and erythro isomers.
従つて、スレオ−あるいはエリスロ−DOPSを
得る為にはいずれかの段階で、スレオ体とエリス
ロ体の分離が必要である。 Therefore, in order to obtain threo- or erythro-DOPS, it is necessary to separate the threo and erythro forms at some stage.
従来、このスレオ体とエリスロ体の分離法とし
ては
(1) スレオ−、エリスロ−３−（３・４−ジベン
ジルオキシフエニル）セリンで分別再結晶を行
う方法（J.Am.chem.Soc.、76、1322
（1954））。 Conventionally, methods for separating the threo and erythro forms include (1) fractional recrystallization with threo, erythro-3-(3,4-dibenzyloxyphenyl)serine (J.Am.chem.Soc ., 76 , 1322
(1954)).
(2) スレオ−、エリスロ−３−（３・４−ジベン
ジルオキシフエニル）−Ｎ−カルボベンズオキ
シセリンのジシクロヘキシルアミン塩で分離す
る方法（特開昭50−49252号公報）。(2) A method of separating threo-, erythro-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine using dicyclohexylamine salt (Japanese Unexamined Patent Publication No. 49252/1983).
が知られている。ところが、(1)の方法は再現性、
および工業的操作の点に難点があり、(2)の方法は
経済的分離法とは言い難い。It has been known. However, method (1) has poor reproducibility and
There are also difficulties in industrial operation, and method (2) cannot be called an economical separation method.
そこで、本発明者等は経済的かつ工業的なスレ
オ−、あるいはエリスロ−３−（３・４−ジベン
ジルオキシフエニル）セリンの分離法を種々検討
した結果、スレオ−、エリスロ−３−（３・４−
ジベンジルオキシフエニル）セリンを鉱酸塩とし
て、スレオ体とエリスロ体との分離を行うという
本発明方法を見出した。 Therefore, the present inventors investigated various economical and industrial separation methods for threo- or erythro-3-(3,4-dibenzyloxyphenyl)serine, and found that threo-, erythro-3-( 3.4-
The present inventors have discovered a method of the present invention in which the threo isomer and the erythro isomer are separated using dibenzyloxyphenyl)serine as a mineral acid salt.
すなわち、本発明方法は３−（３・４−ジベン
ジルオキシフエニル）セリンではエリスロ体がス
レオ体に比べ難溶性であるのに対し、３−（３・
４−ジベンジルオキシフエニル）セリンの鉱酸塩
では水、エタノール、イソプロパノールもしくは
これらの混合溶媒中では溶解性の逆転を伴い、ス
レオ体の鉱酸塩がエリスロ体の鉱酸塩に比べ難溶
性となり、両者の溶解度差がきわめて大であると
いう知見に基づくものである。本発明方法ではス
レオ−、エリスロ−３−（３・４−ジベンジルオ
キシフエニル）セリンを鉱酸により、スレオ体と
エリスロ体の混合物の鉱酸塩として単離してから
溶解度差を利用した分別再結晶法により、相対的
に難溶性のスレオ体の鉱酸塩を結晶として得、必
要に応じこの結晶を除いた溶液を処理することに
より、エリスロ体の鉱酸塩を取得することができ
る。あるいはまた、スレオ−、エリスロ−３−
（３・４−ジベンジルオキシフエニル）セリンの
鉱酸塩の混合物を単離することなくスレオ体の鉱
酸塩とエリスロ体の鉱酸塩とに分離することもで
きる。即ち、スレオ−、エリスロ−３−（３・４
−ジベンジルオキシフエニル）セリンを適当な溶
媒中鉱酸と処理することにより、スレオ体および
エリスロ体の混合物の鉱酸塩は単離することな
く、相対的に難溶性のスレオ体の鉱酸塩を結晶と
して得、必要に応じこの塩を除いた溶液を処理す
ることにより、エリスロ体の鉱酸塩を得ることが
できる。更に必要に応じ前記のようにして得られ
るスレオ体あるいはエスリロ体の鉱酸塩は分解し
て鉱酸を除き対応するスレオ、あるいはエリスロ
−３−（３・４−ジベンジルオキシフエニル）セ
リンにすることができる。 That is, in the method of the present invention, the erythro form of 3-(3,4-dibenzyloxyphenyl)serine is less soluble compared to the threo form, while the erythro form is less soluble than the threo form.
The mineral acid salt of 4-dibenzyloxyphenyl) serine undergoes a reversal of solubility in water, ethanol, isopropanol, or a mixed solvent of these, and the mineral acid salt of the threo form is less soluble than the mineral acid salt of the erythro form. This is based on the knowledge that the difference in solubility between the two is extremely large. In the method of the present invention, threo-erythro-3-(3,4-dibenzyloxyphenyl)serine is isolated as a mineral acid salt of a mixture of threo and erythro forms using a mineral acid, and then fractionated using the difference in solubility. By the recrystallization method, a relatively poorly soluble threo-form mineral acid salt is obtained as crystals, and if necessary, the crystals are removed and a solution is treated to obtain an erythro-form mineral acid salt. Alternatively, threo-, erythro-3-
It is also possible to separate a mixture of mineral acid salts of (3,4-dibenzyloxyphenyl)serine into a mineral acid salt of the threo form and a mineral acid salt of the erythro form without isolating the mixture. That is, threo-, erythro-3-(3・4
- Dibenzyloxyphenyl) serine is treated with a mineral acid in an appropriate solvent to obtain a relatively sparingly soluble mineral acid salt of the threo isomer without isolating the mineral salt of the mixture of the threo and erythro isomers. A mineral acid salt of erythro form can be obtained by obtaining the salt as a crystal and treating a solution from which the salt is removed as necessary. Furthermore, if necessary, the mineral acid salt of threo or esthrillo obtained as described above is decomposed to remove the mineral acid and convert into the corresponding threo or erythro-3-(3,4-dibenzyloxyphenyl)serine. can do.
このように本発明方法によれば、スレオ−、エ
リスロ−３−（３・４−ジベンジルオキシフエニ
ル）セリンに於て、鉱酸塩としてスレオ体とエリ
スロ体とに容易に分離することができる為極めて
有利な分離法を提供することになる。 As described above, according to the method of the present invention, threo-erythro-3-(3,4-dibenzyloxyphenyl)serine can be easily separated into the threo form and the erythro form as mineral acid salts. This provides an extremely advantageous separation method.
従つて、本発明方法によつて得られる生成物、
すなわち、スレオ−、あるいはエリスロ−３−
（３・４−ジベンジルオキシフエニル）セリン、
もしくは各々の鉱酸塩に脱ベンジル化反応を行え
ば対応するスレオ−、あるいはエリスロ−DOPS
を得ることができる為、経済的かつ工業的なスレ
オ−、あるいはエリスロ−DOPSの合成法をも同
時に提供する。 Therefore, the products obtained by the method of the invention,
That is, threo- or erythro-3-
(3,4-dibenzyloxyphenyl)serine,
Alternatively, if each mineral salt is debenzylated, the corresponding threo- or erythro-DOPS can be obtained.
Therefore, an economical and industrial method for synthesizing threo- or erythro-DOPS is also provided.
以下本発明を具体的に説明する。 The present invention will be specifically explained below.
スレオ−、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリンの鉱酸塩の混合物を単
離してから分別再結晶により、スレオ体の鉱酸塩
とエリスロ体の鉱酸塩とに分離する方法では、ま
ずスレオー、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリンの鉱酸塩の混合物を通
常の方法で得る。即ち、スレオ−、エリスロ−３
−（３・４−ジベンジルオキシフエニル）セリン
と１モル比以上の鉱酸から成る溶液を調製し、溶
媒を溜去するか、あるいはこれらの塩が難溶であ
る溶媒を加えることにより、スレオ−、エリスロ
−３−（３・４−ジベンジルオキシフエニル）セ
リンの鉱酸塩の混合物を得ることができる。スレ
オ−、エリスロ−３−（３・４−ジベンジルオキ
シフエニル）セリンのスレオ体とエリスロ体の比
はいくらであつても良い。鉱酸とは塩酸、臭化水
素酸、ヨウ化水素酸または硝酸より成る鉱酸群よ
り任意に選ばれたる鉱酸を意味するが、鉱酸の価
格および取扱い易さの点で塩酸は特に好ましい。 A mixture of mineral acid salts of threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine is isolated and then fractionated recrystallized to form mineral acid salts of threo form and erythro form. In the separation method, a mixture of mineral acid salts of threo and erythro-3-(3,4-dibenzyloxyphenyl)serine is first obtained by a conventional method. Namely, Threo-, Erythro-3
- By preparing a solution consisting of (3,4-dibenzyloxyphenyl)serine and a mineral acid in a molar ratio of 1 or more, and distilling off the solvent, or adding a solvent in which these salts are poorly soluble, A mixture of mineral acid salts of threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine can be obtained. The ratio of the threo isomer and the erythro isomer of threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine may be any value. Mineral acid means any mineral acid selected from the mineral acid group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, or nitric acid, and hydrochloric acid is particularly preferred in terms of price and ease of handling. .
次いで、スレオ体、エリスロ体の鉱酸塩の混合
物を常法により分別再結晶を行うと相対的に難溶
性であるスレオ−３−（３・４−ジベンジルオキ
シフエニル）セリンの鉱酸塩を得ることができ
る。この再結晶溶媒は水、エタノール、イソプロ
パノールもしくはこれらの混合溶媒である。 Next, when a mixture of mineral acid salts of threo form and erythro form is fractionated and recrystallized by a conventional method, a mineral acid salt of threo-3-(3,4-dibenzyloxyphenyl)serine, which is relatively sparingly soluble, is obtained. can be obtained. The recrystallization solvent is water, ethanol, isopropanol, or a mixed solvent thereof.
また、必要に応じこの塩を除いた溶液にエリス
ロ体の鉱酸塩が難溶である溶媒、例えばエーテ
ル、トルエン等を加えるかあるいは濃縮により溶
媒量を減らすか、あるいはまた他の溶媒に変える
ことにより結晶としてエリスロ−３−（３・４−
ジベンジルオキシフエニル）セリンの鉱酸塩を得
ることができる。 In addition, if necessary, add a solvent in which the mineral salt of erythro form is poorly soluble, such as ether or toluene, to the solution from which the salt is removed, reduce the amount of the solvent by concentration, or change to another solvent. As a crystal, erythro-3-(3・4-
A mineral acid salt of dibenzyloxyphenyl)serine can be obtained.
一方、スレオ−、エリスロ−３−（３・４−ジ
ベンジルオキシフエニル）セリンの鉱酸塩の混合
物を単離せずに両者を分離する方法では、スレオ
−、エリスロ−３−（３・４−ジベンジルオキシ
フエニル）セリンと１モル比以上の鉱酸からなる
溶液を調製する。反応および分離工程は適当な温
度で行うことができる。反応および分離は室温で
も充分進行するが、反応および分離を促進させる
為に最初は加温し、次に徐冷後冷することもでき
る。 On the other hand, in the method of separating the mineral acid salts of threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine without isolating the mixture, -dibenzyloxyphenyl)serine and a mineral acid in a molar ratio of 1 or more. The reaction and separation steps can be carried out at any suitable temperature. Although the reaction and separation proceed satisfactorily at room temperature, in order to accelerate the reaction and separation, it is also possible to first heat, then slowly cool, and then cool.
スレオ体の鉱酸塩とエリスロ体の鉱酸塩との溶
解度差により相対的に難溶性である結晶として、
スレオ−３−（３・４−ジベンジルオキシフエニ
ル）セリンの鉱酸塩が得られる。スレオ−、エリ
スロ−３−（３・４−ジベンジルオキシフエニ
ル）セリンのスレオ体とエリスロ体の比はいくら
であつても良い。鉱酸、および溶媒は前述の分別
再結晶時と同様であり、特に好ましい例では鉱酸
として、価格および取扱い易さの点から塩酸が挙
げられる。 As a crystal that is relatively poorly soluble due to the difference in solubility between the mineral salts of the threo form and the mineral salts of the erythro form,
A mineral acid salt of threo-3-(3,4-dibenzyloxyphenyl)serine is obtained. The ratio of the threo and erythro forms of threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine may be any value. The mineral acid and solvent are the same as those used in the above-mentioned fractional recrystallization, and a particularly preferred example of the mineral acid is hydrochloric acid from the viewpoint of cost and ease of handling.
必要に応じ、スレオ体の鉱酸塩を除いた溶液に
エリスロ体の鉱酸塩が難溶である溶媒、例えばエ
ーテル、トルエン等を加えるかあるいは濃縮によ
り溶媒量を減らすか、あるいはまた他の溶媒に変
えることにより結晶としてエリスロ−３−（３・
４−ジベンジルオキシフエニル）セリンの鉱酸塩
を得ることができる。 If necessary, add a solvent in which the erythro mineral salt is poorly soluble, such as ether or toluene, to the solution from which the threo mineral salt is removed, or reduce the amount of the solvent by concentration, or use another solvent. Erythro-3-(3.
A mineral acid salt of 4-dibenzyloxyphenyl)serine can be obtained.
更に必要に応じ上記方法で分離して得られるス
レオ体の鉱酸塩あるいはエリスロ体の鉱酸塩は常
法により分解して対応するスレオ−３−（３・４
−ジベンジルオキシフエニル）セリン、あるいは
エリスロ−３−（３・４−ジベンジルオキシフエ
ニル）セリンを得ることができる。 Furthermore, if necessary, the mineral acid salt of the threo form or the mineral acid salt of the erythro form obtained by separation by the above method is decomposed by a conventional method to obtain the corresponding threo-3-(3.4
-dibenzyloxyphenyl)serine or erythro-3-(3,4-dibenzyloxyphenyl)serine can be obtained.
次に実施例により本発明を説明する。本発明は
もとよりこれに限定されるものではない。 Next, the present invention will be explained with reference to examples. The present invention is of course not limited to this.
実施例 １
スレオ、エリスロ−３−（３・４−ジベンジル
オキシフエニル）セリン（スレオ体：エリスロ体
≒３：１）５ｇをメタノール30mlと３規定塩酸水
10mlに溶解した後、減圧下溶媒を溜去して、スレ
オ−、エリスロ−３−（３・４−ジベンジルオキ
シフエニル）セリン・塩酸塩を得た。この塩をエ
タノールより再結晶してスレオ−３−（３・４−
ジベンジルオキシフエニル）セリン・塩酸塩2.7
ｇ、mp150〜154℃を得た。この塩を除いた溶液
の溶媒を溜去し、イソプロパノールを加え、結晶
としてエリスロ−３−（３・４−ジベンジルオキ
シフエニル）セリン・塩酸塩1.3ｇ、mp136〜140
℃を得た。Example 1 5 g of threo, erythro-3-(3,4-dibenzyloxyphenyl)serine (threo form: erythro form ≒ 3:1) was mixed with 30 ml of methanol and 3N hydrochloric acid water.
After dissolving in 10 ml, the solvent was distilled off under reduced pressure to obtain threo-erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride. This salt was recrystallized from ethanol and threo-3-(3,4-
dibenzyloxyphenyl) serine hydrochloride 2.7
g, mp 150-154°C were obtained. After removing the salt, the solvent of the solution was distilled off, isopropanol was added, and crystals were obtained, 1.3 g of erythro-3-(3,4-dibenzyloxyphenyl) serine hydrochloride, mp136-140.
℃ was obtained.
実施例 ２
スレオ−、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリン（スレオ体：エリスロ
体≒３：１）92ｇにエタノール330mlと濃塩酸35
mlを加え40〜45℃で１時間、室温で1.5時間、氷
冷却下２時間撹拌した。析出した結晶を取し
て、スレオ−３−（３・４−ジベンジルオキフエ
ニル）セリン・塩酸塩61.5ｇ、mp143〜145℃を
得た。この塩を除いた溶液にエーテルを加えて一
夜室温にて放置すると結晶を析出した。取する
ことにより、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリン・塩酸塩7.8ｇ、
mp138〜142℃を得た。続いてこの塩を除いた溶
液の溶媒を溜去し、熱時アセトンを加えてから室
温で放置した。析出した結晶を取し、エリスロ
−３−（３・４−ジベンジルオキシフエニル）セ
リン・塩酸塩10.6ｇ、mp139〜142.5℃を得た。
エリスロ体の塩酸塩は合計18.4ｇ得た。Example 2 92 g of threo, erythro-3-(3,4-dibenzyloxyphenyl)serine (threo form: erythro form ≒ 3:1), 330 ml of ethanol and 35 g of concentrated hydrochloric acid
ml and stirred at 40-45°C for 1 hour, at room temperature for 1.5 hours, and under ice cooling for 2 hours. The precipitated crystals were collected to obtain 61.5 g of threo-3-(3,4-dibenzyloxyphenyl)serine hydrochloride, mp 143-145°C. Ether was added to the solution from which the salt was removed and the mixture was left overnight at room temperature to precipitate crystals. By taking, 7.8g of erythro-3-(3,4-dibenzyloxyphenyl)serine hydrochloride,
mp138-142°C was obtained. Subsequently, the solvent of the solution from which the salt was removed was distilled off, acetone was added while hot, and the solution was left to stand at room temperature. The precipitated crystals were collected to obtain 10.6 g of erythro-3-(3,4-dibenzyloxyphenyl) serine hydrochloride, mp 139-142.5°C.
A total of 18.4 g of erythro hydrochloride was obtained.
実施例 ３
スレオ−、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリン１スレオ体：エリスロ
体≒３：１）１ｇにイソプロパノール15mlと濃塩
酸1.5mlを加え40〜45℃１時間、室温30分、氷冷
却下２時間撹拌した。析出した結晶を取し、ス
レオ体の塩酸塩0.68ｇ、mp145〜148℃を得た。
この塩を除いた溶液の溶媒を溜去後、アセトンを
加え、析出した結晶を取し、エリスロ体の塩酸
塩0.2ｇ、mp128〜132℃を得た。Example 3 15 ml of isopropanol and 1.5 ml of concentrated hydrochloric acid were added to 1 g of threo, erythro-3-(3,4-dibenzyloxyphenyl)serine 1 threo form: erythro form ≒ 3:1) at 40-45°C for 1 hour. The mixture was stirred at room temperature for 30 minutes and then for 2 hours under ice cooling. The precipitated crystals were collected to obtain 0.68 g of threo-isomer hydrochloride, mp 145-148°C.
After distilling off the solvent of the solution excluding this salt, acetone was added and the precipitated crystals were collected to obtain 0.2 g of hydrochloride of erythro form, mp 128-132°C.
実施例 ４
スレオ−、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリン（スレオ体：エリスロ
体≒３：１）７ｇに95％エタノール44mlと濃塩酸
4.4mlを加え実施例３と同様に処理し、スレオ体
の塩酸塩4.1ｇ、mp149〜154℃を得、エリスロ体
の塩酸塩1.7ｇ、mp136〜139℃を得た。Example 4 7 g of threo, erythro-3-(3,4-dibenzyloxyphenyl)serine (threo form: erythro form ≒ 3:1), 44 ml of 95% ethanol, and concentrated hydrochloric acid
4.4 ml was added and treated in the same manner as in Example 3 to obtain 4.1 g of the hydrochloride of the threo form, mp 149-154°C, and 1.7 g of the hydrochloride of the erythro form, mp 136-139°C.
実施例 ５
スレオ−、エリスロ−３−（３・４−ジベンジ
ルオキシフエニル）セリン0.10ｇにイソプロパノ
ール１mlおよび48％臭化水素酸0.20ｇを加えて室
温にて30分間撹拌後氷冷却下４時間撹拌した。析
出した結晶を取し、スレオ体の臭化水素酸塩、
mp153〜154℃、を得た。Example 5 1 ml of isopropanol and 0.20 g of 48% hydrobromic acid were added to 0.10 g of threo-erythro-3-(3,4-dibenzyloxyphenyl)serine, stirred at room temperature for 30 minutes, and then cooled on ice. Stir for hours. The precipitated crystals were collected and the threo form hydrobromide,
mp153-154℃ was obtained.
実施例 ６
鉱酸として57％ヨウ化水素酸0.2ｇを用い、他
は実施例５と全く同様に反応させた。氷冷却下に
エーテルを加えてから析出した結晶を取し、ス
レオ体のヨウ化水素酸塩、mp129〜132℃を得
た。Example 6 The reaction was carried out in the same manner as in Example 5 except that 0.2 g of 57% hydroiodic acid was used as the mineral acid. Ether was added under ice cooling, and the precipitated crystals were collected to obtain a threo-hydriodide salt, mp 129-132°C.
実施例 ７
鉱酸として60％硝酸0.1ml用いる他は実施例５
と全く同様に処理し、スレオ体の硝酸塩、mp127
〜128℃を得た。Example 7 Example 5 except that 0.1 ml of 60% nitric acid was used as the mineral acid.
Treated in exactly the same way as threoform nitrate, mp127
~128°C was obtained.
Claims (1)
ジルオキシフエニル）セリンを鉱酸（ここで鉱酸
とは塩酸、臭化水素酸、ヨウ化水素酸または硝酸
を意味し、以下同じ意味を有する）で処理し得ら
れるスレオ−３−（３・４−ジベンジルオキシフ
エニル）セリンの鉱酸塩とエリスロ−３−（３・
４−ジベンジルオキシフエニル）セリンの鉱酸塩
との水、エタノール、イソプロパノールもしくは
これらの混合溶媒中での溶解度差を利用すること
により、スレオ−３−（３・４−ジベンジルオキ
シフエニル）セリンの鉱酸塩とエリスロ−３−
（３・４−ジベンジルオキシフエニル）セリンの
鉱酸塩とに分離し、必要に応じ各々の鉱酸塩を分
解することにより、対応するスレオ−、あるいは
エリスロ−３−（３・４−ジベンジルオキシフエ
ニル）セリンを得ることを特徴とするスレオ−、
エリスロ−３−（３・４−ジベンジルオキシフエ
ニル）セリンの分離法。1 Threo-, erythro-3-(3,4-dibenzyloxyphenyl)serine with a mineral acid (here, mineral acid means hydrochloric acid, hydrobromic acid, hydroiodic acid or nitric acid; hereinafter the same meaning) The mineral acid salt of threo-3-(3,4-dibenzyloxyphenyl)serine obtained by treatment with erythro-3-(3,4-dibenzyloxyphenyl)
Threo-3-(3,4-dibenzyloxyphenyl) was prepared by utilizing the solubility difference between the mineral acid salt of serine and water, ethanol, isopropanol, or a mixed solvent thereof. ) Mineral acid salts of serine and erythro-3-
(3,4-dibenzyloxyphenyl) serine mineral acid salt and decompose each mineral acid salt as necessary to obtain the corresponding threo- or erythro-3-(3,4- dibenzyloxyphenyl) serine,
Method for separating erythro-3-(3,4-dibenzyloxyphenyl)serine.
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8312877A JPS5419931A (en) | 1977-07-11 | 1977-07-11 | Separation of threo, erythro-3-(3,4-dibenzyloxyphenyl)serines |
| BE189122A BE868797A (en) | 1977-07-11 | 1978-07-06 | PROCESS FOR SEPARATION OF 3- (3,4-DIBENZYLOXYPHENYL) DIASTEREOISOMERIC SERINE |
| AU37870/78A AU516261B2 (en) | 1977-07-11 | 1978-07-07 | Separation of diastereoisomeric 3-(3,4-dibenzyloxy-phenyl) |
| US05/922,665 US4246428A (en) | 1977-07-11 | 1978-07-07 | Method for separation of diastereoisomeric 3-(3,4-dibenzyloxyphenyl)serine |
| GB7829334A GB2000779B (en) | 1977-07-11 | 1978-07-10 | Method for separating diastereoisomers of 3 - (3,4 - dibenzyloxyphenyl)-serine |
| FR7820553A FR2397392A1 (en) | 1977-07-11 | 1978-07-10 | PROCESS FOR SEPARATION OF 3- (3,4-DIBENZYLOXYPHENYL) DIASTEREOISOMERIC SERINE |
| CH753878A CH634824A5 (en) | 1977-07-11 | 1978-07-11 | METHOD FOR SEPARATING DIASTEREOMERS 3- (3,4-DIBENZYLOXYPHENYL) SERINE. |
| CA307,188A CA1100149A (en) | 1977-07-11 | 1978-07-11 | Method for separation of diastereoisomeric 3-(3,4- dibenzyloxyphenyl)serine |
| ES471639A ES471639A1 (en) | 1977-07-11 | 1978-07-11 | Method for separation of diastereoisomeric 3-(3,4-dibenzyloxyphenyl)serine |
| AT499578A AT356646B (en) | 1977-07-11 | 1978-07-11 | METHOD FOR SEPARATING ERYTHRO AND THREO-3- (3,4-DIBENZYLOXYPHENYL) SERINE |
| DE19782830475 DE2830475A1 (en) | 1977-07-11 | 1978-07-11 | PROCESS FOR SEPARATING DIASTEREOISOMERS OF 3-) 3,4-DIBENZYLOXYPHENYL) SERINE |
| IT68640/78A IT1159895B (en) | 1977-07-11 | 1978-07-11 | PROCEDURE FOR THE SEPARATION OF THE DIASTEREOISOMERS OF 3- (3,4-DIBENZYLOXYPHENYL) -SERINE |
| NL7807469A NL7807469A (en) | 1977-07-11 | 1978-07-11 | SEPARATION OF DIASTERY ISOMERS FROM 3- (3,4-DIBENZYLOXY-PHENYL) SERINE. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8312877A JPS5419931A (en) | 1977-07-11 | 1977-07-11 | Separation of threo, erythro-3-(3,4-dibenzyloxyphenyl)serines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5419931A JPS5419931A (en) | 1979-02-15 |
| JPS6131097B2 true JPS6131097B2 (en) | 1986-07-17 |
Family
ID=13793551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8312877A Granted JPS5419931A (en) | 1977-07-11 | 1977-07-11 | Separation of threo, erythro-3-(3,4-dibenzyloxyphenyl)serines |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4246428A (en) |
| JP (1) | JPS5419931A (en) |
| AT (1) | AT356646B (en) |
| AU (1) | AU516261B2 (en) |
| BE (1) | BE868797A (en) |
| CA (1) | CA1100149A (en) |
| CH (1) | CH634824A5 (en) |
| DE (1) | DE2830475A1 (en) |
| ES (1) | ES471639A1 (en) |
| FR (1) | FR2397392A1 (en) |
| GB (1) | GB2000779B (en) |
| IT (1) | IT1159895B (en) |
| NL (1) | NL7807469A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4480109A (en) * | 1982-01-14 | 1984-10-30 | Sumitomo Chemical Company, Limited | Process for producing threo-3-(3,4-dihydroxyphenyl)serine |
| JPS59112949A (en) * | 1982-12-20 | 1984-06-29 | Microbial Chem Res Found | Novel l-threo-adrenalic acid |
| CA1223602A (en) * | 1983-05-25 | 1987-06-30 | Naohito Ohashi | Process for producing 3-(3,4-dihydroxyphenyl) serine |
| WO2004100929A1 (en) | 2003-05-12 | 2004-11-25 | Synergia Pharma, Inc. | Threo-dops controlled release formulation |
| US8158149B2 (en) * | 2004-05-12 | 2012-04-17 | Chelsea Therapeutics, Inc. | Threo-DOPS controlled release formulation |
| US20070010584A1 (en) * | 2003-09-04 | 2007-01-11 | Peroutka Stephen J | Compositions and methods for orthostatic intolerance |
| EP2363123A1 (en) * | 2006-06-28 | 2011-09-07 | Chelsea Therapeutics, Inc. | Pharmaceutical compositions comprising droxidopa |
| ES2480966T3 (en) * | 2007-03-09 | 2014-07-29 | Chelsea Therapeutics, Inc. | Droxidopa and its pharmaceutical composition for the treatment of fibromyalgia |
| CA2686723A1 (en) * | 2007-05-07 | 2008-11-13 | Chelsea Therapeutics, Inc. | Droxidopa and pharmaceutical composition thereof for the treatment of mood disorders, sleep disorders, or attention deficit disorders |
| JP5880913B2 (en) | 2011-05-17 | 2016-03-09 | 三郎 佐古田 | Treatment for trunk symptoms (postural reflex abnormalities) in Parkinson's disease |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3182079A (en) * | 1962-11-19 | 1965-05-04 | Ajinomoto Kk | Optical resolution of dl-valine |
| CH505785A (en) * | 1969-02-07 | 1971-04-15 | Hoffmann La Roche | Process for the preparation of (-) threo-3- (4-Hydroxy-3-methoxyphenyl) -serine |
| US3830836A (en) * | 1970-10-15 | 1974-08-20 | Ajimoto Kk | 3,4-dihydroxyphenylalanine hemihydrochloride |
-
1977
- 1977-07-11 JP JP8312877A patent/JPS5419931A/en active Granted
-
1978
- 1978-07-06 BE BE189122A patent/BE868797A/en not_active IP Right Cessation
- 1978-07-07 US US05/922,665 patent/US4246428A/en not_active Expired - Lifetime
- 1978-07-07 AU AU37870/78A patent/AU516261B2/en not_active Expired
- 1978-07-10 GB GB7829334A patent/GB2000779B/en not_active Expired
- 1978-07-10 FR FR7820553A patent/FR2397392A1/en active Granted
- 1978-07-11 ES ES471639A patent/ES471639A1/en not_active Expired
- 1978-07-11 CA CA307,188A patent/CA1100149A/en not_active Expired
- 1978-07-11 AT AT499578A patent/AT356646B/en not_active IP Right Cessation
- 1978-07-11 IT IT68640/78A patent/IT1159895B/en active
- 1978-07-11 NL NL7807469A patent/NL7807469A/en not_active Application Discontinuation
- 1978-07-11 CH CH753878A patent/CH634824A5/en not_active IP Right Cessation
- 1978-07-11 DE DE19782830475 patent/DE2830475A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| GB2000779A (en) | 1979-01-17 |
| AU516261B2 (en) | 1981-05-28 |
| FR2397392A1 (en) | 1979-02-09 |
| GB2000779B (en) | 1982-01-20 |
| DE2830475A1 (en) | 1979-01-25 |
| JPS5419931A (en) | 1979-02-15 |
| CA1100149A (en) | 1981-04-28 |
| CH634824A5 (en) | 1983-02-28 |
| AT356646B (en) | 1980-05-12 |
| FR2397392B1 (en) | 1982-04-30 |
| IT1159895B (en) | 1987-03-04 |
| NL7807469A (en) | 1979-01-15 |
| ATA499578A (en) | 1979-10-15 |
| ES471639A1 (en) | 1979-02-01 |
| BE868797A (en) | 1979-01-08 |
| IT7868640A0 (en) | 1978-07-11 |
| US4246428A (en) | 1981-01-20 |
| AU3787078A (en) | 1980-01-10 |
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